Organ and cell transplantation represents a promising means of effectively treating a wide range of genetic and acquired diseases. A major challenge in successful organ transplantation is inhibiting the sometimes vigorous immune response mounted by the recipient against donor tissue. This immune attack is orches- trated by CD4+ and CD8+ T cells, which become activated after recognizing alloantigens and receiving appropriate costimulatory signals. One promising therapy designed to regulate the immune response to donor tissue involves the use of reagents designed to block the costimulatory molecules that are required for T cell activation. While this strategy proved very successful in mouse models, attempts to use this therapy to prevent rejection of primate allografts have enountered limitations. The goal of proposal, therefore, is to use novel transgenic systems in which with defined alloantigens to carefully dissect the factors necessary to induce and maintain the state of tolerance induced by costimulation blockade. The proposed experiments will evaluate the contribution of the following factors: 1) the precursor frequency of alloantigen specific CD4+ and CD8+ T cells 2) the relative affinities of these T cells for their peptide:MHC ligand.